The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas

Teri T.B. Ngo, Tien Peng, Xing Jie Liang, Oluwaseun Akeju, Sandra Pastorino, Wei Zhang, Yuri Kotliarov, Jean C. Zenklusen, Howard A. Fine, Dragan Maric, Patrick Y. Wen, Umberto De Girolami, Peter Mc L. Black, Wells W. Wu, Rong Fong Shen, Neal O. Jeffries, Dong Won Kang, John K. Park

Research output: Contribution to journalArticle

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Abstract

Background: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/- malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.

Original languageEnglish (US)
Pages (from-to)639-652
Number of pages14
JournalJournal of the National Cancer Institute
Volume99
Issue number8
DOIs
StatePublished - Apr 18 2007

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Stathmin
Glioma
Oligodendroglioma
Proteins
Confidence Intervals
Loss of Heterozygosity
Neoplasms
Heterografts
Procarbazine
Recurrence
Cell Line
Microtubule-Associated Proteins
Survival
Kaplan-Meier Estimate
Vincristine
Immunoblotting
Proteomics
Transfection

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas. / Ngo, Teri T.B.; Peng, Tien; Liang, Xing Jie; Akeju, Oluwaseun; Pastorino, Sandra; Zhang, Wei; Kotliarov, Yuri; Zenklusen, Jean C.; Fine, Howard A.; Maric, Dragan; Wen, Patrick Y.; De Girolami, Umberto; Black, Peter Mc L.; Wu, Wells W.; Shen, Rong Fong; Jeffries, Neal O.; Kang, Dong Won; Park, John K.

In: Journal of the National Cancer Institute, Vol. 99, No. 8, 18.04.2007, p. 639-652.

Research output: Contribution to journalArticle

Ngo, TTB, Peng, T, Liang, XJ, Akeju, O, Pastorino, S, Zhang, W, Kotliarov, Y, Zenklusen, JC, Fine, HA, Maric, D, Wen, PY, De Girolami, U, Black, PML, Wu, WW, Shen, RF, Jeffries, NO, Kang, DW & Park, JK 2007, 'The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas', Journal of the National Cancer Institute, vol. 99, no. 8, pp. 639-652. https://doi.org/10.1093/jnci/djk135
Ngo, Teri T.B. ; Peng, Tien ; Liang, Xing Jie ; Akeju, Oluwaseun ; Pastorino, Sandra ; Zhang, Wei ; Kotliarov, Yuri ; Zenklusen, Jean C. ; Fine, Howard A. ; Maric, Dragan ; Wen, Patrick Y. ; De Girolami, Umberto ; Black, Peter Mc L. ; Wu, Wells W. ; Shen, Rong Fong ; Jeffries, Neal O. ; Kang, Dong Won ; Park, John K. / The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas. In: Journal of the National Cancer Institute. 2007 ; Vol. 99, No. 8. pp. 639-652.
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abstract = "Background: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/- malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95{\%} confidence interval [CI] = 0 to 90 months), 17 months (95{\%} CI = 10.6 to 23.4 months), and 6 months (95{\%} CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95{\%} CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95{\%} CI = 58.2 to 69.8 days) (difference = 31 days, 95{\%} CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.",
author = "Ngo, {Teri T.B.} and Tien Peng and Liang, {Xing Jie} and Oluwaseun Akeju and Sandra Pastorino and Wei Zhang and Yuri Kotliarov and Zenklusen, {Jean C.} and Fine, {Howard A.} and Dragan Maric and Wen, {Patrick Y.} and {De Girolami}, Umberto and Black, {Peter Mc L.} and Wu, {Wells W.} and Shen, {Rong Fong} and Jeffries, {Neal O.} and Kang, {Dong Won} and Park, {John K.}",
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TY - JOUR

T1 - The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas

AU - Ngo, Teri T.B.

AU - Peng, Tien

AU - Liang, Xing Jie

AU - Akeju, Oluwaseun

AU - Pastorino, Sandra

AU - Zhang, Wei

AU - Kotliarov, Yuri

AU - Zenklusen, Jean C.

AU - Fine, Howard A.

AU - Maric, Dragan

AU - Wen, Patrick Y.

AU - De Girolami, Umberto

AU - Black, Peter Mc L.

AU - Wu, Wells W.

AU - Shen, Rong Fong

AU - Jeffries, Neal O.

AU - Kang, Dong Won

AU - Park, John K.

PY - 2007/4/18

Y1 - 2007/4/18

N2 - Background: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/- malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.

AB - Background: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/- malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.

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